Steroid-dimethylamines and their quaternary halides



United States Patent O STEROlD-DHWETHYLAMINES AND THEIR QUATERNARYHALIDES Percy L. Julian, Maywood, and Helen C. Printy and Edwin W.Meyer, Chicago, 111., assignors to The Glidden Company, Cleveland, Ohio,a corporation of Ohio No Drawing. Application May 19, 1951, Serial No.227,272

4 Claims. (Cl. 260-3975) The present invention relates to17-dimethylamino steroids and their production.

This application is a continuation-in-part of application Serial No.773,526, filed September 11, l9fi7, now Patent No. 2,561,378. In thatapplication there 1s disclosed the preparation of dimethylamines of bothsaturated and unsaturated steroids in which the dimethylamino group iseither attached to the 17-carbon atom or is in a group attached to the17-carbon atom of the steroid nucleus. The instant case is directed tothat portion of the original subject matter pertaining to the17-dimethylamines and covered by original claims 2 and 23 of the parentapplication.

It is accordingly an object of the present invention to provide a methodfor the production of 17-dimethylam1nes of the steroid series.

Another object is to provide 17-dimethylamines of the steroid series.

Other objects will be apparent to those skilled in the art from thefollowing description.

It has been found that the dimethylamines of the present invention canbe prepared by the reductive methylation of the corresponding 17-aminewith formaldehyde and formic acid. Thus, amines of the type R-NHz, whereR is a cyclopentanopolyhydrophenanthrene nucleus and the NH2 group isattached to the 17-carbon atom of the nucleus may be readily methylatedto the compounds of the type We have found that the quaternary ammoniumhalides of the dimethylamines of the present invention, and particularlythe iodides, possess bacteriostatic properties against gram positiveorganisms.

The following examples are illustrative of the invention.

, EXAMPLE I 3-hydroxy-5-androstene-17-dimethylamine 25 g. of3-hydroxy-5-androstene-17-amine was added with cooling and shaking to 24cc. of 90% formic acid. The slurry became brown. Then 17 cc. of 3538%aqueous formaldehyde was added and the mixture was heated for four hoursunder reflux on the steam cone. The solid dissolved with copiousevolution of C02. The solution was concentrated under vacuum to a thicksirup which was taken up in a mixture of ether and 5% aqueoushydrochloric acid. The acidic layer was made basic with sodium hydroxideand the amine extracted with ether. The ether solution was washedseveral times with water,

dried and concentrated to about 150 cc. After chilling,

the separated solid was filtered and washed with petroleum ether.Another crop was obtained from the mother llquor. There resulted 19.0 g.of white crystalline 3-hydroxy- 5-androstene-l7-dimethylamine, M. P.208213 C.

EXAMPLE II 3-ket0-17-dimethylamino-4-androstene A solution of 3,6 g. of3-keto-4-androstene-l7-amine acetate in 3.6 g. of formic acid and 2.6 g.of 35% aqueous formaldehyde was heated on the steam bath under refluxfor four hours. Carbon dioxide was liberated. The 11quid was dilutedwith sodium carbonate solution and extracted with benzene-chloroform.The extract was washed with water followed by dilute hydrochloric acid.The

.was dissolved in 130 cc. of acetone.

2,705,238 Patented Mar. 29, 1955 See vated alumina.

EXAMPLE HI 3-acetoxy-5-temorcholenyldimethylamine A mixture of 20.5 g.of 3-acetoxy 5 ternorcholenylamine acetate, 17.85 g. of formic acid and35% aqueous formaldehyde was heated on a steam bath for five hours.Carbon dioxide was liberated at the beginning of the heating period. Themixture was diluted with water. After the addition of ether and dilutehydrochloric acid, the mixture was shaken and the aqueous layercontaining suspended insoluble hydrochloride was separated. The aqueoussuspension was made alkaline with dilute sodium carbonate solution andextracted with ether. The extract was washed with water and dried. Uponremoval of solvent, there remained 17.8 g. of crude 3-acetoxy-5-ternorcholenyldimethylamine, M. P. 153-l75 C. Recrystallization fromether gave pure material melting at EXAMPLE IV3-acet0xy-all0-tern0rcholanyldimethylamine 4.2 g. of3-acetoxy-allo-ternorcholanylamine acetate was mixed with 3 g. of 90%formic acid and 2 g. of 35 aqueous formaldehyde solution and heated on asteam bath for four hours. The solution was then concentrated undervacuum, diluted with 5% hydrochloric acid and ex tracted with ether. Theacidic aqueous layer was made alkaline with 10% sodium hydroxidesolution and extracted with ether. The ether extract was washed withwater and dried. The residue remaining after removal of solvent wascrystallized from benzene. The crude 3-acetoxy-allo-ternorcholanyldimethylamine melted at 147- EXAMPLE V3a,]Zu-diacetoxy-ternorcholanyldimethylamine The acid chloride wasprepared from 7.2 g. of 311,120:- diacetoxy-bisnorcholanic acid and 4.2cc. of thionyl chloride in 20 cc. of dry benzene-40 cc. of dry ether.After one hour the solvent was removed and the acid chloride Thissolution was treated, dropwise, at 0-5 C. with a solution of 2.3 g. ofsodium azide in 10 cc. of water. The mixture was stirred for twentyminutes and the azide precipitated by the addition of 200 cc. of coldwater. The solid azide was separated, suspended in cc. of 80% aqueousacetic acid and decomposed by heating to 50-60 C. for one hour. Theclear solution was steam distilled, neutralized with dilute sodiumcarbonate solution and extracted With ether. The washedand dried ethersolution gave upon concentration 6.2 g. of crude3u,l2a-diacetoxy-ternorcholanylamine, acetamide derivative, M. P.220-221 C.

The crude aminewas methylated by heating 5.2 g. in 6 cc. of 90% formicacid and 4 cc. of 35% aqueous formaldehyde on the steam bath underreflux for four hours. The orange liquid was poured into cold dilutesodium hydroxide and extracted with ether. The ether solution was washedwith water, dried and concentrated under vacuum. The resulting amorphousmaterial, 3.5 g., was crystallized from petroleum ether, B. P. 35-60 C.,yielding small needles of 3a,12a-diacetoxy-ternorcholanyldimethylaminemelting at 134l37 C.

From the foregoing examples, it is apparent that the reductivemethylation may be carried out on compounds possessing a wide variety ofsubstituents attached to nuclear carbon atoms. It will be understoodthat various modifications may be made therein without departing fromthe spirit and scope of the invention. Thus, various acyloxy derivativesother than the acetoxy, such as the propionoxy, benzoxy, etc.derivatives, may be employed, as well as compounds possessing ketogroups in the 11- or 12-positions, since the invention is not dependenton the presence or absence of such groups.

Also, when producing a hydroxy-dimethylamine, it may be desirable toesterify the hydroxy group before carrying out subsequent reactions,especially those which are d1- rected to the introduction of additionalhydroxy groups. In some instances it may be desirable to treat thisgroup with reagents which would also react on other OH groups, ifpresent. By esterifying hydroxy groups present in the dimethylamine,subsequent preferential csterification can be avoided. Any suitable acidmay be used for this purpose.

Moreover, when treating compounds containing keto groups, it isdesirable to employ the amine in the form of a salt, such as is shown inExample II, in order to prevent condensation of the keto group with theNH2 group to form a Schiffs base. Any suitable acid may be used in thiscase to form the salt.

Having described the invention, what is claimed is: 1. The process whichcomprises subjecting a primary 17-amino-steroid to a reductivemethylation with formaldehyde and formic acid to form a l7-dimethylamino5 steroid.

References Cited in the file of this patent UNITED STATES PATENTSBockmuhl July 7, 1942 Marker Aug. 4, 1942

1. THE PROCESS WHICH COMPRISES SUBJECTING A PRIMARY 17-AMINO-STEROID TOA REDUCTIVE METHYLATION WITH FORMALDEHYDE AND FORMIC ACID TO FORM A17-DIMETHYLAMINO STEROID.